4-chloro-11alpha, 17alpha-dihydroxypregnanes



United States Patent 2,772,299 4-CHLOR0-110,17a-DllHYDROXYPREGNANES Gunther S. Fonken, Kalamazoo, Robert H. Levin, Kalamazoo Township, Kalamazoo County, and A Vern McIntosh, .lr., Kalamazoo, Micla, assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application July 16, 1952, Serial No. 299,231

9 Claims. (Cl. 260-397.4)

This invention relates to steriod compounds, and is more particularly concerned with novel and useful 4- chloro-3-ketosteroids.

The 4-chloro-3-ketosteroids of the present invention are those of the formula wherein R1 is a-hydroxy or an acyloxy ester thereof, such as for example, formyloxy, acetoxy, benzoyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, benzoyloxy, phenylacetoxy, octanoyloxy, or the like, especially lower-alkanoyloxy; R is hydrogen or hydroxy; and R3 is acetyl, acyloxyacetyl, e. g., acetoxyacetyl, propionoxyacetyl, butyryloxyacetyl, benzoyloxyacetyl, octanoyloxyacetyl, or the like, especially acyloxyacetyl wherein the acyloxy group is a lower-alkanoyloxy group, or haloacetyl, e. g., bromoacetyl, chloroacetyl, or the like.

It is an object of the present invention to provide the 4-chloro-3-ketosteroids of the above formula. Other objects of this invention will be apparent to those skilled in the art to which this invention pertains.

4-chloro-3-ketosteroids are valuable precursors to physiologically active steroids since they can be dehydrohalogenated by procedure well-known in the art, to produce A -3-ketosteroids. Most physiologically active hormone and hormone-like steriods are A -3-ketosteroids. Moreover, 4 -chloro-3ketosteroids are very stable and can be stored for long periods of time without noticeable decomposition. Other uses and advantages of this invention will be apparent to those skilled in the art to which this invention pertains.

Preferred starting compounds for the present invention are 3-hydroxysteroids having the normal configuration at the S-carbon atom, which are unsubstituted at the 4- position, which are saturated (i. e., carbon to carbon double and triple-bonds are not present), and which do not have unsubstituted primary or secondary hydroxyl groups other than the 3-hydroxyl group, since these unsaturated linkages and hydroxyl groups, which also usually react with organic hypochlorites, sometimes unduly complicate the reaction. Steroids of the above type, but containing, in addition, an 11a(0r ,8)-hydr0xyl group, are also included as preferred starting compounds since the 1106- hydroxyl group usually is unaffected by alkyl hypochlo rites, and the ll,6-hydroxyl group is smoothly converted to an ll-ketonic oxygen by using two additional molar equivalents of the alkyl hypochlorite. This delineation of preferred starting compounds, however, is not to be 2,772,299 Patented Nov. 27, 1956 construed as limiting the scope of this invention. Other 3-hydroxy steroids which are converted to 4-ch1or'o-3- ketosteroids by the process of this invention are also included as starting materials within the scope of this in vention. If additional groups such as, for example, unsaturated linkages or other hydroxyl. groups, or other groupings, are present which are reactive with the alkyl hypschlorite under the conditions of the reaction, an additional amount of the organic hypochlorite may be included in the reaction mixture to react with these ad ditional groups. Alternatively these additional reactive groups in the starting compounds may be protected and later regenerated in the product obtained by the process of the present invention, for example, carbon to carbon double-bonds may be protected by adding two bromine atoms and later regenerated by treating with zinc. Additional hydroxyl groups may be protected, for example, by selective ester or ether formation and later regenerated by hydrolysis. In some instances chlorination occurs at a position other than the 4-position, e. g., at the 2- position when a 3-hydroxya'llosteroid is employed as starting material.

Preferred starting normal 3cz(O1 fi)-hydroxysteroids of particular interest are those having the following structural formula:

wherein R is ot-hydroxy or B-hydroxy; R1 is hydrogen, whydroxy or an acyloxy ester thereof, such as, for example, formyloxy, acetoxy, benzoyloxy, propionoxy, butyryloxy, valeryloxy, hexanoyloxy, phenylacetoxy, octanoyloxy, or the like, especially lower-alkanoyloxy, or p-hydroxy, or ketonic oxygen; R2 is hydrogen or hydroxy; R3 is acetyl, acyloxyacetyl, e. g., acetoxyacetyl, propionoxyacetyl, butyryloxyacetyl, octanoyloxyacetyl, benzoyloxyacetyl, or the like, especially acy'loxyacetyl wherein the acyloxy group is a lower-alkanoyloxy group, or haloacetyl, e. g., bromoacetyl, chloroacetyl, or the like.

According to the method of the present invention, a 3-hydroxysteroid is contacted, in the presence of water, with an organic hypochlorite, and preferably with an alkyl hypochlorite.

In carrying out the process of the present invention, a 3-hydroxysteroid is contacted, in the presence of from a trace to about twenty percent of water based upon the total weight of the reaction mixture, with an organic hypochlorite, preferably an alkyl hypochlorite. The reaction is usually conducted in the presence of an organic solvent such as, for example, tertiary-butyl alcohol, tertiary-amyl alcohol, choroform, ethylene dichloride, or the like, the concept, definition, and use of a solvent being well-known in the art. The employed temperature is usually between about minus ten and about plus fifty degrees centigrade, ordinarily at about room temperature, e. g., between about twenty and about thirty degrees centigrade, for a reaction period of between about ten minutes and about twenty-four hours, the exact time required for complete reaction being in part dependent upon the reaction temperature and the particular hypochlorite and solvent employed, as well as other factors apparent to one skilled in the art.

Although the use of organic hypochlorites generally is within the purview of the present invention, alkyl hypochlorites are usually used. The secondary-alkyl hypochlorites, however, are relatively unstable and for this reason are not the preferred hypochlorites. Since methyl hypochlorite is extremely unstable and even explosive in certain instances, it is preferably not employed in carrying out the process of the present invention. The tertiary-alkyl hypochlorites have been found to be particularly satisfactory organic hypochlorites, being quite sta ble, and of these, tertiary-butyl hypochlorite has been used with repeated success and is therefore a preferred alkyl hypochlorite. Best yields of the desired 4-chloro- 3-ketosteroids appear to be obtained when the alkyl hypochlorite is employed in the molar ratio to starting 3-hydroxysteroid of at least about two to one, preferably from about 2.2 to about 2.5 moles of alkyl hypochlorite to one mole of starting steroid. Large molar excesses of alkyl hypochlorite do not appear to be advantageous and may even be disadvantageous in certain instances. However, if an additional group which reacts with the alkyl hypochlorite is present, the amount of alkyl hypochlorite is increased by the amount required to react with the additional group.

While considerably broader ranges of reaction temperature, e. g., between about minus ten and about plus fifty degrees centrigrade, are included within the scope of the present invention, the preferred reaction temperature is at or about room temperature, e. g., between about twenty and about thirty degrees centrigrade, as high yields of desired product are obtained at this temperature and external cooling or heating is usually unnecessary. Sometimes, however, a reaction temperature slightly below room temperature will enhance the yield of desired product when the reaction is unduly accompanied by undesirable side reactions. Usually reaction temperatures substantially above room temperature are not preferred. In general the preferred reaction temperature, while usually room temperature, varies somewhat with the starting steroid and the alkyl hypochlorite employed. Temperatures substantially below minus ten and substantially above plus fifty degrees centigrade are operative in certain instances.

Tertiary alkanols have been found to be excellent reaction solvents and tertiary-butyl alcohol, a preferred solvent, has been used with repeated success. Other solvents such as, for example, tertiary-amyl alcohol, chloroform, ethylene dichloride, pentane, hexane, and the like, are also suitable. The choice of reaction solvent depends in part on the solubility of the starting steroid in the solvent.

The presence of water is an important factor in carrying out the process of the present invention. Water is, therefore, always present in the reaction mixture, from 0.5 percent to about twenty percent of the total reaction mixture by weight being the usual operating limits. When only a trace of water is present, the yields of desired product are less than optimum, and when more than twenty percent water, based on the total reaction weight is employed, the reaction is usually sluggish and requires long periods of time for completion of the reaction. Usually about two to about six percent water gives the best yields of product.

It has also been found that the addition of a strong acid such as, for example, hydrochloric, sulfuric, benzenesulfonic, para-toluenesulfonic acid, or the like, and particularly hydrochloric acid, to the reaction mixture enhances the yield of desired product and preferred operating conditions include the addition of from about 0.5 mole to about 1.5 moles of hydrochloric acid per mole of steroid to the reaction mixture. The reaction can be carried out in the presence or absence of light.

Isolation of the desired product of the reaction is conveniently achieved by distilling the volatile components of the reaction mixture at reduced pressure, leaving the steroid product as the distillation residue. Quite frequently, especially when using tertiary-butyl alcohol as reaction solvent, the desired reaction product crystallizes from the reaction mixture in a state of high purity and does not require further purification. Purification of the reaction product can be achieved, however, if desired, by crystallization from a solvent such as, for example, methanol, ethanol, ether, chloroform, methylene dichloride, or the like, or by adsorption and elution on a chromatographic column according to methods Wellknown in the art.

The progress of the oxidation can conveniently be followed by iodmetric titration, according to methods known in the art, of aliquot samples taken from time to time from the reaction mixture. When consumption of alkyl hypochlorite has essentially ceased or when the theoretical amount has been consumed, the reaction is usually complete and further reaction time is unnecessary.

An especially preferred method of carrying out the process of the present invention involves dissolving the selected S-hydroxysteroid in a solvent, preferably tertiary-butyl alcohol, and contacting the solution with from about 2.2 to about 2.5 molar equivalents of an alkyl hypochlorite, preferably tertiary-butyl hypochlorite, in the presence of from about 0.5 to about 1.5 molar equivalents of dilute hydrochloric acid for from about ten minutes to about twenty-four hours. When the reaction is complete, the solvent may be distilled at about room temperature at reduced pressure and the steroid product obtained as the distillation residue.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting.

PREPARATION 1.-3 OL,17CL-DIHYDROXYPREGNANE-1 1,20- DIONE ZO-ETHYLENE GLYcoL KETAL A mixture of 260 milligrams of 3a,17a-dihydroxypregnane-11,20-dione [Kritchevsky, Garmaise, and Gallagher, I. Am. Chem. Soc. 74, 483 (1952)], five mi1li liters of ethylene glycol, fifty milligrams of para-toluenesullonic acid monohydrate and milliliters of benzene was placed in a reaction flask which was equipped with a reflux condenser and a water trap so arranged that the condensed vapors passed through the water trap before returning to the reaction flask. The mixture was heated to reflux and was allowed to reflux for five hours while at the same time being agitated. The water which formed was removed by co-distillation with benzene and was collected in the water trap. The reaction mixture was cooled and poured into a dilute solution of sodium bicarbonate. The benzene layer was separated, washed with Water, dried and concentrated to dryness. The residue was chromatographed over forty grams of Florisil magnesium silicate using eighty-milliliter portions of a mixture of ethylene dichloride with successively greater proportions of acetone for elution. The material, which was eluted with ethylene dichloride-acetone (12:1 and 8:1), weighed 141 milligrams after removal of the solvents. Recrystallization from benzene-Skelly Solve B gave fifty milligrams of 3a,l7cx-dihydroxypregnane-11,20-

dione ZO-ethylene glycol ketal melting at 144 to 146 degrees Centigrade.

Analysis.Calculated for czsHscOs: C, 70.37; H, 9.25. Found: C, 70.65; H, 9.28.

PREPARATION 2.3 a,1 10C,17OL-TRIHYDROXYPREGNAN-ZO- ONE AND 3:1,11/3,l7oc-TRlHYDROXYPREGNANQO-ONE To a solution of two grams of lithium aluminum hydride in 200 milliliters of anhydrous ether was added dropwise, with stirring, two grams of 3u,l7a-dihydroxypregnane 11,20 dione 20 ethylene glycol ketal from Preparation 1 in twenty milliliters of anhydrous benzene. The mixture was then stirred at room temperature for one hour followed by boiling under reflux for an additional hour. With continued stirring the resulting mixture was cooled and treated cautiously with water added dropwise. The resulting solution containing the 311,1l,17ot-trihydroxypregnan--one 20-ethylene glycol ketals then was admixed with a ten-fold excess of dilute hydrochloric acid and the resulting heterogeneous mixture was stirred vigorously for twenty hours at room temperature. The product was isolated by separating the organic and aqueous layers, extracting the aqueous layer with ether, combining the ether extract with the organic layer, washing the organic solution twice with water, drying the washed solution over anhydrous sodium sulfate, removing the drying agent by filtration, removing the solvents by distillation under reduced pressure, dissolving the resulting residual oil in ethyl acetate, and adding Skelly Solve B to give an opalescent solution. The crystals obtained (crop A), 540 milligrams, were removed by filtration, and an additional quantity of Skelly Solve B was added to the filtrate. The crystals obtained from the diluted filtrate (crop B) were separated by filtration weighed 590 milligrams. An additional quantity of crystals identical with those of crop B was obtained from the remaining mother liquor by distillation of the solvents under reduced pressure, redissolving the residual oil in a minimum amount of ethyl acetate, and diluting with Skelly Solve B.

Crop A was recrystallized twice from a mixture of ethyl acetate and Skelly Solve B and once from a mixture of acetone and Skelly Solve B to give 240 milligrams of 3a,11a,17oc trihydroxypregnan 20 one as needles; melting point 184-186 degrees centigrade; [M Plus 52 degrees in acetone.

Analysis:

Calculated for CzrHsrOr: C, 71.9; H, 9.71 Found: C, 72.2; H, 9.53 C, 72.3; H, 9.66

Crop B was recrystallized once from a mixture of ethyl acetate and Skelly Solve B and once from a mixture of acetone and Skelly Solve B to give 275 milligrams of 3u,11,B,17a trihydroxypregnan 20 one as plates; melting point 213-216 degrees centigrade; [M plus 73 degrees in acetone.

Analysis-Calculated for C21Hs404: C, 71.9; H, 9.71. Found: C, 72.1; H, 9.81.

PREPARATION 3.3 fl-ACETOXYPREGNANE-l 1,20-DIONE 3/3 hydroxypregnane 11,20 dione [von Euw, Lardon, and Reichstein, Helv. Chim. Acta., 27, 821 (1944)], 8.18 grams, was dissolved in a mixture of fifty milliliters of acetic anhydride and two milliliters of pyridine, and the resulting solution was allowed to stand at room temperature for 24 hours. The mixture was then poured into 325 milliliters of water and allowed to stand at room temperature for several hours to permit decomposition of the excess acetic anhydride. The solid product was removed by filtration and dried under vacuum. Two recrystallizations from aqueous acetone gave 2.75 grams, melting point 155-162 degrees centigrade. Repeated recrystallization from aqueous acetone gave 3/i-acetoxypregnane-11,20-dione; melting point 164-165 degrees centigrade; [M plus 99 degrees in chloroform. Analysis:

Calculated for C23H34O4: C, 73.90; H, 9.10 Found: C, 73.69; H, 9.02 C, 73.64; H, 8.77

PREPARATION 4.-3;3',11,2O-TRiAcEToxY-9(11),17(20)- PREGNADIENE A mixture of 2.75 grams of 3 8-acetoxypregnane-11,20- dione from Preparation 3, 0.73 gram of para-toluene sulfonic acid monohydrate, and ninety millilters of acetic anhydride was heated to boiling and allowed to distil slowly for three hours, 71 milliliters of distillate being collected. Another fifteen milliliters of distillate was collected by distillation under reduced pressure, and the resulting residue was cooled, diluted with 85 milliliters of ether, washed with one percent aqueous sodium bicarbonate solution and with water, and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the ether was removed by distillation giving 3.5 grams of 313,11,20-triacetoxy9(11),17(20)- pregnadiene as a glass.

PREPARATION 5.17(20)-ox1no-35,1 l,20-TRIACETOXY 9 1 1 -PREGNENE 36,11,20 triacetoxy 9(ll),17(20) pregnadiene, 3.5 grams, from Preparation 4 was dissolved in seventeen milliliters of chloroform and the resulting solution cooled to a temperature of zero to five degrees centigrade. A mixture of milligrams of anhydrous sodium acetate and 7.7 milliliters of 38 percent paracetic acid was added with stirring, the temperature of thte reaction mixture being maintained at zero to five degrees centigrade. The resulting mixture was stirred at this temperature for ten minutes, then allowed to come to room tempera ture, and stirred for an additional ninety minutes. The mixture then was diluted with eighty milliliters of ether, washed with four fifteen-milliliter portions of five percent aqeuous sodium hydroxide solution, and three fifteenmilliliter portions of water, and dried over anhydrous Removal of the drying agent by filtration and distillation of the solvents under reduced pres sure gave 3.5 grams of 17(20)-oxido-3/3,11,20-triacetoxy sodium sulfate.

9(l1)-pregnene as a viscous oil.

PREPARATION 6.-3 p, 17 ot-DIHYDROXYPREGNANE-l 1,20- DIoNE The 17(20)oxide-36,11,20-triacetoxy-9(11)-pregnene from Preparation 5, 3.5 grams, was dissolved in 66 milliliters of alcohol, 66 milliliters of 0.5 normal aqueous sodium hydroxide solution added, and the resulting mixture stirred for thirty hours at room temperature under a nitrogen atmosphere. The mixture was poured into 250 milliliters of water, and the resultant slurry extracted with four fifty-milliliter portions of chloroform. Distillation of the extraction solvent gave 2.74 grams of crude 3,8,17a-dihydroxypregnane-11,20-dione.

PREPARATION 7 .-3 ,8, 1 7ot-DIHYDROXYPREGNANE-1 1,20- nroNE 20-ETHYLENE GLYcoL KETAL In the same manner as given in Preparation 1, 35,17a-dihydroxypregnane-11,20-dione 20-ethylene glycol ketal is prepared from 3,8,17ot-dihydroxypregnane- 11,20-dione from Preparation 6 by reaction with ethylene glycol in the presence of para-toluenesulfonic acid.

PREPARATION 8.-3,B, 1 1a,170t-TRIHYDROXYPREGNAN-20- ONE AND 3,3,11B,170tTRIHYDROXYPREGNAN20-0NE PREPARATION 9.1 lot-HYDROXYPROGESTERONE A medium was prepared from five milliliters of corn steep liquor, twenty grams of Edamine commercial lactalbumin digest, and fifty milligrams of Cerelose commercial dextrose, per liter of tap water and adjusted to a pH of between about 5.5 and about 5.9. To four liters of this medium containing a 32 to 48 hour growth, at room temperature with aeration, of Rhizopus arrhizus, was added one gram of progesterone in fifty milliliters were used to develop the column.

I 7 of acetone. The culture was then incubated at room temperature for 48 hours. At the end of this time the pH of the medium was 3.5 and the fermentation liquor and mycelia were extracted successively with three oneliter portions, one two-liter portion, and one one-liter portion of methylene chloride. The methylene chloride extracts were combined and washed with two 400-milliliter portions of two percent aqueous sodium bicarbonate solution and three SOD-milliliter portions of water. The methylene chloride extract was evaporated to dryness in vacuo and the solids taken up in fifty milliliters of methylene chloride. The solution was transferred to a 100- milliliter beaker and evaporated by a stream of air. The solids, weighing 1.585 grams, were dissolved in five milliliters of hot methanol and allowed to cool slowly at room temperature, whereupon 75 milligrams o-f crystals separated out. The mother liquor was freed of solvent by aeration, dissolved in fifty milliliters of benzene, and chromatographed over alumina (A1203). Fifty grams of acid-washed alumina, dried at 45 degrees centigrade, was used as adsorbent and 100-milliliter portions of solvents The solvents and the order used were as follows: benzene, benzene, benzene plus percent ether, benzene plus 5 percent ether, benzene plus percent ether, benzene plus 10 percent ether, benzene plus 10 percent ether, benzene plus 50 percent ether, benzene plus 50 percent ether, ether, ether, ether plus 5 percent chloroform, ether plus 5 percent chloroform, ether plus 10 percent chloroform, ether plus 10 percent chloroform, ether plus 50 percent chloroform, ether plus 50 percent chloroform, chloroform, chloroform, chloroform plus 5 percent acetone, chloroform plus 5 percent acetone, chloroform plus 10 percent acetone, chloroform plus 10 percent acetone, chloroform plus 50 percent acetone, chloroform plus 50 percent acetone, acetone, acetone, acetone plus 5 percent methanol, acetone plus 5 percent methanol, acetone plus 10 percent methanol, acetone plus 10 percent methanol, acetone plus 50 percent methanol, acetone plus 50 percent methanol. The chloroform and chloroform plus five percent acetone .eluates were combined, evaporated to dryness, and the residue dissolved in two milliliters of hot methanol and filtered. After overnight refrigeration, 171 milligrams of crystalline lla-hydroxyprogesterone, melting at 166 to 167 degrees centigrade, was obtained. A sample recrystallized from methanol gave the following constants: melting point, 166-167 degrees centigrade [o1] plus 175.9 degrees (chloroform).

Analysis.Calculated for CziHsnOs: C, 76.4; H, 9.10. Found: C, 76.6; H, 8.92.

The structure of this product was further established by its conversion, with chromic acid in acetic acid, to ll-ketoprogesterone EReichstein, Helv. Chim. Acta., 23, 684 (1940); ibid. 26, 721 (1943)].

PREPARATION 10.-1 loc-HYDROXYPREGNANE-3,20-DIONE A solution of 250 milligrams of lla-hydroxyprogesterone from Preparation 9 in 100 milliliters of ethanol containing six drops of triethylamine was subjected to hydrogenation at room temperature under a pressure of about ten pounds of hydrogen in the presence of 45 milligrams of a thirty percent palladium-charcoal catalyst in a Parr apparatus with an auxiliary mercury manometer. The time required for the hydrogenation was about twenty minutes. The reaction mixture was filtered and the solvent was evaporated to yield 265 milligrams of material melting at 145-185 degrees centigrade. This product was extracted with a mixture of one milliliter of ether and nine milliliters of Skelly Solve B. On standing, the extract deposited eighty milligrams (32 percent) of l1a-hydroxypregnane-3,20dione as feathery needles which melted at 85-90 degrees centigrade. Recrystallization from a mixture of about six drops of ethyl acetate and five milliliters of Skelly Solve B did not change the melting point.

Analysis.-Calculated for C21H32O3: C, 75.86; H, 9.70. Found: C, 76.13; H, 9.63.

PREPARATION 1 1 .-3 11,1 loc-DIHYDROXYPREGNAN-ZO-ONE To a solution of 5.31 grams of lla-hydrdxypregnane- 3,20-dione of Preparation 10 in milliliters of peroxidefree dioxane maintained at fifty degrees centigrade in a water bath was added a solution of 195.5 milligrams of sodium borohydride (assay 84 percent) in five milliliters of water. The mixture was stirred for one hour at fifty degrees centigrade, filtered, acidified with three normal aqueous hydrochloric acid solution, and evaporated under reduced pressure. The residue was crystallized from fifty milliliters of ethyl acetate to give 1.95 grams (36 percent) of 301,11a-dihydroxypregnan-20-one, which melted at 180-182 degrees centigrade. An additional 0.2 gram melting at 181-183 degrees centigrade was obtained from the filtrate, total yield, 2.15 grams (40 percent).

PREPARATION 12.1 11:1-AcET0xYPREGNANE-3 ,20-DIONE A mixture of 70.5 milligrams of lla-hydroxypregnane- 3,20-dione from Preparation 10, 0.8 milliliter of acetic anhydride and 0.7 milliliter of pyridine was allowed to stand for sixteen hours at room temperature and then poured into ice water. The precipitated product was isolated by filtration and dried. The yield of 111:1- acetoXypregnane-S,20-dione, melting at 1435-1465 degrees centigrade, was 67 milligrams (84 percent). After one recrystallization from ether-Skelly Solve B, the melting point was -151 degrees centigrade; [a] =plus 63 degrees (c=0.803 in chloroform).

Analysis.Ca1culated for C23H34O4: C, 73.76; H, 9.15. Found: C, 73.93; H, 9.32.

In the same manner, other llot-acyloxypregnane-3,20- diones are prepared from 11whydroxypregnane-3,20-dione, including 111:1-formyloxypregnane-3,20-dione (using formic acid as the acylating agent); 11e1-propionoxypregnane-3,20-dione; 1la-butyryloxypregnane-3,ZO-dione; 11aoctanoyloxypregnane-3,20-dione; and the like.

PREPARATION 13 .-3 111,1 10,20-TRIACETOXY-17 (20) PREGNENE PREPARATION 14.3 B, 1 11x,20-TRIAcET0xY-1 7 (20 PREGNENE Using the procedure described in Preparation 13, 3/3- hydroxy-lIa-acetoxypregnan-ZO-one (prepared by the reduction of the 11-1z-acetoxypregnane-3,20-dione of Preparation 12 with hydrogen at two to three atmospheres pressure in methanol at room temperature using a Raney nickel catalyst), is converted to 3,8,ll1x,2Otriacetoxy- 17(20)-pregnenc with acetic anhydride in the presence of para-toluenesulfonic acid.

In the same manner as given above in Preparation 13 and Preparation 14, other 31x(or ,8),11o1,2O-triacyloxy- 17(20)-pregnenes are prepared, including 31x,111x,20-tripropionoxy 17(20) pregnene; 3,B,lloz,20 tripropionoxy 17(20) pregnene; 35,20 diacetoxy 11/9 formyloxy 17(20 pregnene; 36,20 dipropionoxy 111xacetoxy 17(20) pregnene; 3a,l1oc,20 trioctanoyloxy- 17( 20) pregnene; 35,20 dioctanoyloxy 111x propionoxy-17( 20) -pregnene; 301,1 1o1,2O-tributyroyloxy-17(20) pregnene; 3a,11a,20 trivaleroyloxy 17 (20) pregnene; 3ot,llu,20-trihexanoyloxy 17(20) pregnene; 3a,11ot,20- triheptanoyloxy 17(20) pregnene; and 3a,1lot,20 trioctanoyloxy-17 20) -pregnene.-

PREPARATION 15 .--17 20)-OXIDO-3ot,l 10:,20- TRIACETOXYPREGNANE One and one-half grams of 30z,llot,20 -triacetoxy 17(20)-pregnene (Preparation 13) was dissolved in 7.5 milliliters Of chloroform, and the solution was cooled in an ice bath to about five degrees centigrade. Three and three-tenths milliliters of commercial grade forty per cent peracetic acid solution in which 100 milligrams of sodium acetate had been dissolved was added, and the resulting mixture was then shaken on a mechanical shaking machine for about two hours at room temperature to complete the reaction. The mixture containing the crude product was diluted with fifty milliliters of methylene chloride and then washed with several 25-milliliter portions of ice-cold five percent aqueous sodium hydroxide solution followed by 25-mil1i liter portions of water until the wash solution was neutral to pH test paper. The neutral solution was dried with anhydrous sodium sulfate and then filtered to remove the drying agent. The White crystalline residue obtained on evaporating the solvent from the clear, dry solution melted at 210 213 degrees centigrade. Recrystallization from a mixture of ethyl acetate and Skelly Solve B gave fiuffy needles of 17 (20) -XldO-3oc,l :,20-triacetoxypregnanc, melting at 214-217 degrees centigrade.

Analysis:

Calculated for CZ'ZH lOO'II C, 68.04; H, 8.46 Found: C, 68.33; H, 8.62 C, 67.90; H, 8.38

PREPARATION 16.--17(20)OXIDO-3,3,1lot-20- TRIACETOXYPREGNANE Using the procedure described .in Preparation 15, 3 3, 1lm,20-triacetoxy-l7(20)-pregnene from Preparation 14 is converted to 17(20)-Oxido 3,8,1la,20 triacetoxypregname by oxidation With peracetic acid in the presence of sodium acetate.

In the same manner as given above in Preparation 15 and Preparation 16, other l7(20)-oxido-3u(or 5),11a,20- triacyloxy pregnanes are prepared from the the corre sponding 3a(or {3),l1a,20 triacyloxy 17(20) pregnenes, including 17(20)-OXid0-3oc,110c,20 -tripropionoxypregnane; 17(20) Oxido 313,1 la,20 tripropionoxypregnane; lltx-acetoxy 313,20 dipropionoxy l7(20)-oxidopregnane; 11a formyloxy 35,20 diacetoxy 17(20) oxidopregnane; 17(20) oxido 3oc,l1ot,20 tzioctanoyloxypregnane; 313,20 dioctanoyloxy 17(20) OXid0-11apropionoxypregnane; 17(20) OXido 3a,11ot,20 tributyryloxypregnane; 17(20) oxido 3a,11a,20 trivaleryloxypregnane; 17(20) oxido 3a,l1a,20 trihexanoyloxypregnane; 17(20) oxido 3a,lla,20 triheptanoyloxypregnane; 17 (20) oxido 30C,110t,20 trioctanoyloxypregnane; and the like.

PREPARATION 17.-1 10t-ACETOXY-3 a, 17 ot-DIHYDROXYPREG- NAN-ZO-ONE AND 3ot,11a,17a-TiznrYnROxYPREoNAN-20- ONE Nine hundred milligrams of 17(20)-0XidO-3oc,11oz,20- triacetoxypregnane (Preparation 15) was dissolved in fifty milliliters of alcohol, and to the resulting solution was added with swirling 11.3 milliliters of a 0.5 normal aqueous sodium hydroxide solution. After standing at room temperature for thirty minutes, the solution was extracted with chloroform, and the chloroform extract was then washed with twenty percent aqueous sodium chloride solution and dried with anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was removed by evaporation under reduced pressure giving the product as a colorless, viscous oil. The oil was dissolved in 100 milliliters of benzene, and

the solution was passed through a chromatographic col umn packed with ninety grams of Florisil magnesium silicate to absorb the product. The product was eluted from the column by washing with the following solvent mixtures in succession: Ten IOU-milliliter portions of 5 percent acetone and percent Skelly Solve B, ten rnilliliter portions of 10 percent acetone and 90 percent Skelly Solve B, and ten IOU-milliliter portions of 20 percent acetone and 80 percent Skelly Solve B. On evaporation of the solvents from the various fractions, the product had been separated into two parts, both colorless viscous oils. The product from the first fractions was l1ot-acetoxy-3u,17ot-dihydroxypregnan-ZO-one, as confirmed by analytical data, and the product from the later fractions was 311,1la,l7a-trihydroxypregnan20-one, identical with the 3a,llot,l7a-trihydroxypregnan20-one Obtained in Preparation 2. The ratio was about one part of the acetoxy compound for every nine parts of the trihydroxy compound.

Analysis of 1lwacetoXy-3a,17a-dihydroxypregnan-ZO-one:

Calculatedfor CzaHssOs: C, 70.37; H, 9.25 Found: C, 70.30; H, 9.30

PREPARATION 18.1 1ix-AcEToxY-3e,17u-nIHYnnOxYPREo NAN-ZO-ONE AND 3,8,1lot,l7oc-TRIHYDROXYPREGNAN-20- ONE Using the procedure described in Preparation 17, an alcohol solution of 17(20)-oxido 3,6,1 1oz,20 triacetoxypregnane (Preparation 16) was converted by treatment with an aqueous sodium hydroxide solution to an oily product which was separated into 1lm-acetoxy-3B,17adihydroxypregnan 20 one and 3,8,11tx,l7o trihydroxypregnan-ZO-one, as confirmed by analytical data. The ratio was about one part of the acetoxy compound for every ten parts of the trihydroxy compound.

Analysis of 11tx-acetoxy-3B,17a-dihydroxypregnan-20-One:

Calculated for Casi-13005: C, 70.37; H, 9.25 Found: C, 70.43; H, 9.19

Analysis of 3,6,11a,l7tx-trihydroxypregnan-20-one:

Calculated for C21H34O4: C, 71.96; H, 9.78 Found: C, 71.80; H, 9.82

In the same manner as given above in Preparation 17 and Preparation 18, other 11a-acyloxy-3u(or fi),17-dihydroxypregnan-ZO-ones are prepared, including 3a,l7a-dihydroxy 11a formyloxypregnane 20 one; 30,17adihydroxy 11a propionoxypregnan 20 one; 3fi,l7- dihydroxy 11cc propionoxypregnan 20 one; butyryloxy 3a,17 dihydroxypregnan 20 one; 30:,17- dihydroxy 11a valeryloxypregnan 20 one; 311,17- dihydroxy 11a hexanoyloxypregnan 20 one; 3a,17- dihydroxy 11m heptanoyloxypregnan 20 one; 30:,17- dihydroxy 1104 Octanoyloxypregnan 20 one; and the like, depending on the starting material employed.

PREPARATION 19.--21-BRoMO-3 04,1 1 ca, 17 ot-TRIHYDROXY- PREGNAN-ZO-ONE 311,1la,l7a-trihydroxypregnan-ZO-One (Preparation 2 or 17), dissolved in chloroform, is treated with a solution of bromine in chloroform at about forty degrees centigrade. After completion of the bromination, the chloroform is distilled to give a theroretical yield of 2l-bromo- 3a,11a,17a-trihydroxypregnan-20-one; melting point 122.5 to 127 degrees Centigrade.

PREPARATION 20.21-BROMO-3ot, 1 15, 17 ot-TRIHYDROXY- PREGNAN-ZO-ONE 30,11,8,17ot-trihydroxypregnan-ZO-one (Preparation 2), brominated as in Preparation 19 yields 2l-bromo-3ot,llfl, 17a trihydroxypregnan 20 one in nearly quantitative yield.

PREPARATION 21.21-BROMO-3 {3,1 10:, l7oc-TRIHYDROXY- PREGNAN-ZO-ONE Bromination of 35,11a,17a-trihydroxypregnan-ZO-one (Preparation 8 or 18) using the procedure of Preparation 19 gives 21-'bromo-3,8,1la,17ot-trihydroxypregnan-ZO-one in high yield.

PREPARATION 22.2 1 -'BROMO3(3, 1 1,8,170c-TRIHYDROXY- PREGNAN-ZO-ONE Treatment of 3,8,11,8,17rx-trihydroxypregnan-2i)-one (Preparation 8) with bromine in chloroform, according to the procedure of Preparation 19 yields 2l-bromo-3fi, 11p,17atrihydroxypregnan-20-one.

PREPARATION 23.Z1-BROMO-l loc-ACETOXY-3ot, 170c- DIHYDRQXYPREGNAN-ZO-ONE 1la-acetoxy-iia-17a-dihydroxypregnan-20-one (Preparation 17) brominated by the method of Preparation 19 gives a nearly quantitative yield of 21-bromo-11ot-acetoxy 3a,17adihydroXypregnan-ZO-one.

In the same manner, other Zl-bromo-l 1a-acyloxy-3a, 17a-dihydroxypregnan-20ones are prepared from corresponding 11a-acyloxy-3a,17a-dihydroxypregnan-20 ones, including 21-bromo-1 la-forrnyloxy-fm,17wdihydroxypregnane-20-one; 2l-bromo-1 lwpropionoxy-Sa, l7oc-dihYdIOX- ypregnan 20 one; 21-bromo-11 x-butyryloXy-3a-17rx-dihydroxypregnan-ZO-one; 21-bromo-11o-valeryloxy-3o,17adihydroxypregnan-ZO-one; 21-bromo-11whexanoyloxy-3a, 17m-dihydroxypregnan-20-one; 21-bromo-1 la-heptanoyloxy-3a,17a-dihydroxypregnan-ZO-one; 21-bromo-11a-octanoyloxy-3a,17a-dihydroxypregnan-20-one; and the like.

PREPARATION 24.--21-BR0Mo-1 1 oa-ACETOXY-Bfi, 170c- DII-IYDROXYPREGNAN-ZO-ONE Bromination of 11a-acetoxy-3 B,17a-dihydroxypregnan- 20-one (Preparation 18), using the method of Preparation 19, gives 21-bromo-11a-acetoXy-3fi,17a-dihydroxy- Pregnan-ZQ-one in nearly theoretical amounts.

In the same manner other 21-bromo-1loc-acyloxy-3fi,- 17oi-dihydroxypregnan-ZO-ones are prepared from corresponding lloc acyloxy-3,8,17u-dihydroxypregnan-ZO-ones, including 21-br0mo-11a-formyloXy-3p,17x-dihydroxypregnan-ZO-one; 21 bromo 11a propionoxy 3 B,17u-dihydroxypregnan-ZO-one; 21 bromo-l 1u-butyryloxy-3 {117adihydroxypregnan-ZO-one; 21 brorno-11u-valeryloxy-3B,- 17a dihydroxy-pregnan-ZO-one; 21-bromo-11a-hexanoyloxy-3/3,17a-dihydroxypregnan-ZO-one; 21-bromo-1 lwheptanoyloXy-3B,l7a dihydroxypregnan 20 one; 2l-bromo- 11u-octanoyloxy-3fl,l7a-dihydroxypregnan 2O one; and the like.

PREPARATION 25 .'2l-CHLORO-3ot, 1 10,17a- TRIHYDROXYPREGNAN-ZO-ONE A solution of 3a,11a,17rx-trihydroxypregnan-ZO-one (Preparation 2 or 17) in carbon tetrachloride is treated with chlorine, dissolved in carbon tetrachloride, at about room temperature. Distillation of the carbon tetrachloride solvent gives 2l-ChlO1O-3a,l10,17OL-l11lhydl'OXyPI'6gnari-ZO-one in excellent yield.

In the same manner other 21-chlor0-3,l7u-dihydroxy- 1l-oxygenated-pregnan-ZO-ones are obtained from corresponding 3,17a-dihydroxy-1 1-oxygenated-pregnan-20-one including 21-chloro-3a,115,17a-trihydroXypregnan-20-one; 21 chloro 3/3,ll0,17ot trihydroxypregnan 20 one; 21 chloro 3,B,llfl,170t trihydroxypregnan 20 one; 21 chloro 11a acetoxy :,17a dihydroxypregnan 20-one; 21 -chloro-1 1a-propionoxy-3 a, l 7ot-dihydroxypregnan-20-one; 21 chloro-llu-butyryloxy-ii u,17u-dihydroxypregnan-20-one; Zl-Cl'llOI'O-l1ot-V8l61'yl0XY-30C,170c-dll1ydroxypregnan-ZO-one; 21-chloro-11a-hexanoyloxy-3a,17udihydroxypregnan-ZG-one; 21-chloro-1 ltX-hCPiBIlOYlOXY- 3a, 1 711.-dihydroxypregnan-ZQ-one; 21-chloro-1lot-octanoylmay-3a,17a-dihydToXypregnan-ZO-one; 21-chloro-11e-formyloxy-3fl,'17u-dlhydroxypregnane-ZO-one; 21-chloro-11ctacetoxy-Bfi,17zx-dihydroxypregnan-ZG-one; Zl-chloro-l 1 ozpropionoxy-3B,17a-dihydrOXypregnan-ZO-Qne; 21 chloro- 1 1. a-butyiyloxy-3 5, 1 7a-dihydroxypregnan-20-one; 21-chloro-ilu-valeryloxy-35,17a-dihydroxypregnan-ZO-one; 21-

chloro lloc -l1exanoyloxy 35,170 dihydroxypregnan ZO-one; 21 chloro-l 1a-heptanoyloXy-3fl,17a-dihydroxypregnan-ZO-one; 21-chloro-11ot-octanoyloxy-p,17a-dihydroXypregnan-20-one; and the like.

PREPARATON 26.21-AcEToxY-3 05,1 1oc,17oc- TRIYHDROXYPREGNAN-ZO-ONE 2lb10II10-3a,l 1a,17a-trihydroxypregnan-ZO-one (Preparation 19), dissolved in acetone is heated for about sixteen hours under reflux with excess anhydrous potassium acetate in the presence of a trace of potassium iodide and a trace of acetic acid. The resulting solution is cooled and then diluted with water to precipitate the 21- acetoxy 3a,11a,17 x trihydroxypregnan 20 one; melting point 185 to 189 degrees Centigrade. The yield is nearly quantitative.

In the same manner other 21-acyloxy-3a,11a,17o-trihydroxypregnan-20-ones are prepared from 21-bromo-3a, ,l7a-trihydroxypregnan-20-one, and the appropriate potassium acylate, including 2l-f0rmyloXy-3a,1loc,17atrihydroXypregnan-20-one; 2 1 -propionoXy-3 11,1 1OL,17OL-tllhydroxypregnan-ZO-one; 21-butyryloXy-3 0.,1 1a, 17a-trihydroxypregnan-ZO-one; 21-valeryloXy-3 11,1 10:,170c-tIihYdIOX- ypregnan-ZO-one; 21-hexanoyloxy-3 u,11u,17u-trihydroxypregnan-ZO-one; 21-heptan0yloxy-3 u,1 1a, l7oc-l1lhYd1OXY- pregnan-ZO-one; 21-octanoyloXy-3a,11a,17a-trihydroxypregnan-20-one; and the like.

PREPARATION 27 .-21-AcETOxY-3 a, 1 1 e, 1700- TRIHYDROXYPREGNAN-ZO-QNE Replacement of the bromine atom in 21-bromo-3a,1l,8, 17wtrihydroXypregnan-ZO-one (Preparation 20) by an acetoxy group is accomplished in the same manner as in Preparation 26. The yield of 21-acet0Xy-3a,11fl,17atrihydroxypregnan-20-one is the theoretical amount.

In the same manner other 21-acyloXy-3a,115,17wtrihydroxypregnan-ZO-ones are prepared from 2l-bromo- 311,11,8,17wtrihydroxypregnan-ZO-one and the appropriate potassium acylate, including 21 forn1yloxy-3a,11;3,17a-trihydroxypregnan-ZO-one; 21-propionoxy-3a,11B,17o-trihydrQXypregnan-ZO-one; 2 l-butyryloxy-3 04,1 1B,17atrihydroxypregnan-ZO-one; 21 valeryloxy 3m,1 15,1701 trihydroxypregnan-ZO-one; 2 l -heXan0yloX.y-3 (1,1 1 B, 17oc-t1'ihY- droxypregnan-ZO-one; 21-heptanoyloxy3oc,11fi,17a-trihydroxypregnan-20-one; 21-octanoyloXy-3a,11/3,17v.-trihydroXypregnan-ZO-one; and the like.

PREPARATION 28 .-2 1-ACETOXY-3 ,8, 1 1 a, 17 oz,

TRIHYDROXYPREGNAN-ZQ-ONE 21-bron1o-3B, 1 101,17u-trihydroxypregnan-ZO-one (Preparation 21) is converted to 21-acetoxy-3fi,11ot,l7a-trihydroxypregnan-ZO-one by the method of Preparation 26.

In the same manner other 21-acyloXy-3/3,11a,17a-trihydroxypregnan-ZO-ones are prepared from 2l-brom0-3/3, 11a,17a-trihydroxypregnan-ZO-one and the appropriate potassium acylate, including 21-formloxy-3fi,11a,17a-trihydroxypregnan-ZO-one; 21propionoXy-3B, 1 106,1706-111'lhY- droxypregnan 20 one; 21 butyryloxy 3B,1lot,l7utrihydroxypregnan 20 one; 21 valeryloxy 3,8,11a,17utrihydroxyprcgan 2O one; 21 hexanoyloxy 35,1101, 1700 trihydroxypregnan 20 one; 21 heptanoyloxy- 3B,1loz,l7oc trihydroxypregnan 20 one; 21 octanoyloxy 3[3,llo,17oc trihydroxypregnan 20 one; and the like.

PREPARATION 29.-21-AcEToXY-3fl, 1 113, 17a- TRIHYDROXYPREGNAN-ZO-ONE According to the procedure of Preparation 26, 21- bromo 313,115,170 trihydroxypregnan 20 one (Preparation 22) is converted to 21 acetoXy 3fl,ll,8,l7oc trihydroxypregnan 20 one in high yield.

In the same manner other 21-acyloxy-3,@,11fi,l7a-tri hydroxypregnan 2t) ones are prepared from 21 bromo- 3fi,11fi,17o trihydroxy'pregnan 20 one and the appropriate potassium acylate, including 21 formloxy- Still/3,170: trihydroxypregnan 2O one; 21 propion oxy 3,8,11fi,17a trihydroxypregnan 2O one;'21- buty'ryloxy 3B,ll,l7oa trihydroxypregnan 2O one;

13 21 valeryloxy 35,115,1711 trihydroxypregnan 20 one; 21 hexanoyloxy 35,115,1701 trihydroxypregnan 20- one; 21 heptanoyloxy 35,115,1701 trihydroxypregnan- 20 one; 21 octanoyloxy 35,115,1701 trihydroxypregnan 20 one; and the like.

PREPARATION 30.-1 101,21-DIAcETxY-3 01,17 01- DIHYDROXYPREGNAN-ZO-ONE Using the method of Preparation 26, 1101,21-diacetoXy- 301,1701 dihydroxypregnan 20 one is produced from 21 bromo 1101 acetoxy 311,1701 dihydroxypregnan- 20 one (Preparation 23).

In the same manner other 1101,21 diacyloxy 301,1701- dihydroxypregnan 20 ones are prepared from the appropriate 21 bromo 1101 acyloxy 301,1701 dihydroxypregnan 20 one and the appropriate potassium acylate, including 21 acetoxy 1101 formloxy 301,1701 dihydroxypregnan 20 one; 21 proprionoxy 1101 acetoxy- 301,1701 dihydroxypregnan 20 one; 21 butyryloxy- 1101 acetoxy 301,1701 dihydroxypregnan 20 one; 21- valeryloxy 1101 acetoxy 301,1701 dihydroxypregnan- 2O one; 21 hexanoyloxy 1101 acetoxy 301,1701 dihydroxypregnan 20 one; 21 heptanoyloxy 1101 acetoxy 301,1701 dihydroxypregnan 20 one; 21 octanoyloxy 1101 acetoxy 301,1701 dihydroxypregnan 20 one; 1101,21 dipropionoxy 301,1701 dihydroxypregnan 20 one; 1101, 21 dibutyryloxy 301,1701 dihydroxypregnan- 20 one; 1101,21 dihexanoyloxy 301,1701 dihydroxypregnan 20 one; 1101,21 dioctanoyloxy 301, 1701 dihydroxypregnan 20 one; 21 acetoxy 1101 propionoxy-301,1701-dihydroxypregnan-ZO-one; and the like.

PREPARATION 31.-1 101,21-D1AcB'roxY-35,1701- DIHYDROXYPREGNAN-ZO-ONE 21 bromo 1101 acetoxy 35,1701 dihydroxypregnan 20 one (Preparation 24) is treated with potassium acetate according to the procdure of Preparation 26 to give 1101, 21 diacetoxy 35,1701 dihydroxypregnan 20 one in high yield.

In the same manner other 1101,21 diacyloxy 35,1701- dihydroxypregnan 20 ones are prepared from the ap propriate 21 bromo 1101 acyloxy 35,1701 dihydroxypregnan 20 one and the appropriate potassium acylate, including 21 formyloxy 1101 acetoxy 35,1701 dihydroxypregnan 20 one; 21 propionoxy 1101 acetoxy- 35,1711 dihydroxypregnan 20 one; 21 butyryloxy- 1101 acetoxy 35, 1701 dihydroxypregnan 20 one; 21 valeryloxy 1101 acetoxy 35,1701 dihydroxypregnan 20 one; 21 hexanoyloxy 1101 acetoxy 35,1701- dihydroxypregnan 20 one; 21 heptanoyloxy 1101- acetoxy 35,1711 dihydroxypregnan 20 one; 21 octanoyloxy 1101 acetoxy 35,1701 dihydroxypregnan- 20 one; 1101,21 dipropionoxy 35,1701 dihydroxypregnan 20 one; 1101,21 dibutylryloxy 35,1701 dihydroxypregnan 20 one; 1101,21 dihexanoyloxy 35, 1701 dihydroxypregnan 20 one; 1101, 21 dioctanoyloxy 35,1701 dihydroxypregnan 20 one; 21 acetoxy- 1101 propionoxy 35,1701 dihydroxypregnan 20 one; and the like.

The 21-acyloxysteroids obtained in Preparation 26 through Preparation 31 from the 21-bromosteroids may also be obtained in the same manner by substituting the corresponding 21-chlorosteroid (Preparation 25) for the 21-bromosteroid specified.

Example 1 .4-chl0r0-1701-hydr0xypregnane-3,11, ZO-trione A solution of 25 grams of 301,1701-dihydroxypregnane- 11,20-dione [Sarett, I. Am. Chem. Soc., 70, 1454 (1948)] in 380 milliliters of tertiary-butyl alcohol is admixed with five milliliters of concentrated hydrochloric acid and twelve milliliters of water, and thereafter cooled to about fifteen degrees centigrade. Eighteen milliliters (2.2 molar equivalents) of tertiary-butyl hypochlorite is then added thereto, whereupon the temperature rises to about 26 degrees .centigrade. The reaction mixture is stirred for 4.5

hours although the iodometric titration of an aliquot sample taken from the reaction mixture after two hours shows the reaction to be essentially complete. The volatile components of the reaction mixture then are removed by distillation under reduced pressure leaving a 24.6 gram residue a yield of 91 percent of the theoretical, corrected for the samples taken from the reaction mixture for iodometric titrations) of 4-chloro-1701-hydroxypregnane- 3,11,20-trione which melts without purification at 220 to 225 degrees centigrade and has an [011 of plus 91 degrees (acetone).

in the same manner 35,1711-dihydroXypregnane-11,20- dione (Preparation 6) is converted to 4-chloro-1701-hydroxypregnane-3 ,1 l,20-trione. 4chloro-1701-hydroxypregnane-3,11,20-trione is a stable, readily purifiable compound having a well defined crystalline structure. Unlike 4 brorno 1701 hydroxypregnane 3,11,20 trione, said compound does not decompose on standing and is storable for long period without decomposition. Treatment of said compound with semicarbazide hydrochloride and thereafter with pyruvic acid is productive of the known 1701 hydroxy 4 pregnene 3,11,20 trione EKritcheVsky, et al., I. Am. Chem. Soc.., 74, 483 (1952)]. Treatment of 4 chloro 1701 hydroxypregnane 3,11,20- trione with bromine in acetic acid is: productive of 4-- chloro 1701 hydroxy 21 bromopregnane 3,11,20- trione, which, as shown in Example 6, can be converted to cortisone acetate in two steps.

Example 2.4-chl0r0-1701-hydroxypregnane- 3,] 1,20-tri0ne A solution of 0.86 gram (2.5 millimoles) of 301,1701- dihydroxypregnane-l1,20-dione in fifty milliliters of tertiary-butyl alcohol containing 1.5 milliliters of water and 0.2 milliliter of concentrated hydrochloric acid is treated with 1.1 milliliters (10 millimoles) of tcrtiary-butyl hypochlorite for 20.5 hours. The 4 chloro 1701 hydroxypregnane 3,11,20 trione which precipitates is recovered by filtration and melts with decomposition at 234 to 235 degrees centigrade. The infrared spectrum is consistent with the assigned structure.

Analysis.Calculated for Found: Cl, 9.24.

Example 3.4-chl0r0-1701-hydr0xy-21-acet0xypregnane- 3,11,20-trione To a solution of 0.50 gram of 30.,1701-dil1ydroxy-21- acetoxypregnane-l1,20-dione [Sare-tt, I. Am. Chem. Soc, 70, 1454 (1948)] in eighteen milliliters of tertiary-butyl alcohol is added 0.75 milliliter of water, 0.1 milliliter of concentrated hydrochloric acid, and 0.52 milliliter (0.5 gram, 3.69 millimoles) of tertiary-butyl hypochlorite. The resulting solution is diluted to 25 milliliters with tertiarybutyl alcohol and the whole stirred in the dark for about 22 hours. The crystalline precipitate of 4- chl0ro-1701-hydroxy-21-acetoxypregnane-3,11,20-trione is then filtered, Washed with a small portion of tertiary butyl alcohol and air-dried. The yield of precipitated product melting with decomposition at 232 to 236.5 degrees centigrade and having an [01] of plus 99 degrees (acetone) is 0.325 gram, a yield of 60.2 percent of the theoretical. The infrared spectrum is consistent with the assigned structure. A further quantity of product remains in the filtrate and is recovered therefrom.

-4-chloro 1701 hydroxy-21 acetoxypregnane 3,11,20- trione is dehydrohalogenated by treatment with semioarbazide hydrochloride followed by treatment with py-ruvic acid to obtain cortisone acetate.

C21H29O4C1: Cl, 9.31.

Example 4 .--4-ch Zora-1 701-hydr0xy -21 -11cet0xy pregnant?- 3,11,20-tri0ne In exactly the same manner as described in Example 3, using the same reactants but omitting the hydrochloric acid, 4chloro-1701-hyclroxy-2l acetoxypregnanefi,11,20- trione precipitates from the reaction mixture in a yield of 48.1 percent of the theoretical. A further quantity of Example 5 .-4-chl0r0-1 7-hydraxy-21 acetxypregnane- 3,11,20-tri0ne In exactly the same manner as described in Example 3 and using the same reactants but substituting fifty milligrams of para-toluenesulfonic acid for the hydrochloric acid, 4-chloro-17a-hydroxy-2l-acetoxypregnane, 3,11,20- trione precipitates from the reaction mixture in a yield of 51 percent of the theoretical amount. As in Examples 2 and 3, more product is isolated from the remaining filtrate.

In the same manner as shown in Example 3 through Example 5, other 4-chloro-17ot-hydroxy-2laacyloxypregnane-3,11,20-triones are prepared from corresponding 3,17u-dihydroxy-21-acyloxypregnane-11,20-dione, including 4-0hl01'O-170c hydroxy 21 formyloxypregnane- 3, 1 1,20-trione; 4-chloro-17a-hydroxy-2l-propionoxypregname-3 ,1 1,20-trione; 4-chloro-17a-hydroxy-2 l-butyryloxypregnane-3,11,20-trione; 4-chloro-17a-hydroxy-2l-valeryloxyp regnane 3,11,20 trione; 4 chloro-17a-hydroxy-2lhexanoyloxypregnane 3,11,20 trione; 4-chl0ro-17u-hydroxy-21-heptanoyloxypregnane-3,11,20-trione; 4-chloro- 17a-hydroxy-21-octanoyloxypregnane-3,11,20 trione; and the like.

Example 6 .4-chl0r0-1 7a-hydr0xy-21-br0m0pregnane- 3,11,20-tri0ne vA solution of two grams of 3a,17u-dihydroxy-2l-bromopregnane-11,20-dione [Kri-tchevsky, et al., I. Am. Chem. Soc., 74, 483 (1952)] in fifty milliliters of tertiary-butyl alcohol containing 1.5 milliliters of water and 0.38 milliliter of concentrated hydrochloric acid is contacted with 1.12 milliliters of tertiary-butyl hypochlor-ite for 3.5 hours, at the end of which time the hypochlorite is completely consumed. The solution is then diluted with twice its volume of water whereupon the theoretical 2.17 grams of 4-chloro-17a-hydroxy-21-bromopregnane-3,1 1,20-trione precipitates.

Analysis.Calculated for Cz1H2aClBrO4: Total halogen, 25.10. Found: Total halogen, 24.42.

4-chloro-17a-hydroxy-21-bromopregnane-3, 1 1,20-trione also is obtained in exactly the same manner as above using the same reactants but substituting tertiary-amyl hypochlorite for the tertiary-butyl hypochlorite.

4-chloro-17a-hydroxy-21-bromopre-gnane-3 ,11,20trione is a stable compound and does not decompose on standing. The presence of a halogen atom at carbon atom four and at carbon atom 21 renders the compound a valuable precursor to known physiologically active cortical hormones. Dehydroh alogenation with semicarbazide hydrochloride followed by pyruvic acid gives 17a-hydroxy-21- bromo-4-pregnene-3,11,20 trione. Subsequent treatment with potassium acetate .in acetone gives cortisone acetate.

Example 7.4,21-dichl0r0-17a-hydroxypregnane-3J1,20- trione Treatment of 3a,17a-dihydroxypregnane-11,20-dione [Shrett, I. Am. Chem. Soc., 70, 1954 (1948)] with chlorine in acetic acid is productive of 30:,17ct-dlhYdIOXY- 21-chloropregnane-11,20-dione.

In the same manner as described in Example 1, reacting 3a,17a-dihydroxy-2l-chloropregn'ane-l1,20-dione with tertiary-butyl hypochlorite in tertiary-butyl alcohol in the presence of water and hydrochloric acid is productive of 4,211ddi-chloro-17a-hydroxypregnane-3,11,20-trione in high y1e 4,21-dichloro-17a-hydroxypregnane-3,11,20-trione is a stable, well-defined crystalline solid which does not decompose on standing. Dehydroh alogenation followed by treatment with potassium acetate gives cortisone acetate as in Example 6.

Example 8.-4-chl0r0-11ot-hydroxypregnane-3,2O-dione Using the procedure of Example 1, 3a,11a-dihydroxypregnan-ZO-one (Preparation 11) is converted to 4-chloro- 11a-hydroxypregnan-3,ZO-dione. Dehydrohalogenation of the product with pyridine yields the known Ila-hydroxyprogesterone.

Example 9.4-chZora-17-hydraxypregnane-3J1,20-

trione In the same manner :as described in Example 1, a solution of 350 milligrams of 3a,11fi,17a-trihydroxypregnan- 20-one (Preparation 2) in fifteen milliliters of tertiary butyl alcohol was reacted with 0.22 gram of tertiary-butyl hypochlorite in the presence of water and hydrochloric acid. After ten minutes, all the active chlorine of the reaction mixture had been consumed. The solvent was then distilled at reduced pressure and the theoretical 380 milligram residue recrystallized from isopropyl alcohol to give 4- chloro-17a-hydroxypregn ane-3,11,20 tri0ne, identical with the product of Example 1, and which did not depress the melting point of an authentic sample, the yield being almost the theoretical amount.

In the same manner as shown above, 3,8,11fi,17owtrihydroxypregnan-20-one (Preparation 8) is converted to 4 cl1loro- 1 7a-hydroxypregnane-3 ,11,20-trione.

Example I 0.4-ch Zora-1 1 u,17a-dihydr0xypregnane- 3,20-dz'0ne To a solution of 3a,11a,17u-trihydroxypregnane-20- one (Preparation 2 or 17) in aqueous tertiary-butyl alcohol containing hydrochloric acid is added tertiary-butyl hypochlorite, and, after mixing, the resulting solution is allowed to stand at room temperature with occasional shaking, the procedure of Example 3 being followed. After the theoretical amount of tertiary-butyl hypochlorite is reacted, as determined by iodometric titration, the product begins to precipitate. The crystalline 4-chloro- 11a,l7u-dihydroxypregnane-3,20-dione is recovered by filtration. The remainder of the product is obtained as a solid residue when the remaining filtrate is evaporated, the total yield being nearly the theoretical amount; melting point 183 to 185 degrees Centigrade.

Analysis.Calculated for C21H31O4Cl: Cl, 9.26. Found In the same manner 3&11a,17a-trihydroxypregnan-20- one (Preparation 8 or 18) is converted to 4-Cl1l01O-11oc,17udihydroxypregnane-3,20-dione. Mild oxidation of 4- chloro 1104,1711 dihydroxypregnane 3,20 dione with chromic acid in acetic acid solution gives 4-chloro-17uhydroxypregnane-3,11,20-trione (Example 1).

Example 11.4-chl0r0-Z1 a-acet0xy-17a-hydr0xypregnane-3,20-di0ne 11a acetoxy-3u,17a-dihydroxypregnan20-one (Preparation 17) is transformed, according to the method of Example 1, into 4-chloro-11u-acetoxy-17a-hydroxypregnane-3,20-dione, the yield being about the theoretical amount. In the same manner 11u-acetoxy-3fl,17a-dihydroxypregnan-ZO-one (Preparation 18) gives 4-chlorolla-acetoxy 17a hydroxypregnane-3,20-dione; melting point 232 to 234 degrees Centigrade; [011 plus 33 degrees (in acetone).

Analysis-Calculated for CzsHsaOsCl: Cl, 8.34. Found:

In the same manner other 4-chloro-11a-acyloxy-17ahydroxypregnane-3,20-dio11es are prepared from acyloxy-3a(or fi) 17a-dihydroxypregnan-ZO-ones, including 4 chloro-l1a-formyloxy-17a-hydroxypregnane-3,20- dione; 4-chloro-11o-propionoxy 17a hydroxypregnane- 3,20-dione; 4-chloro L 11a butyryloxy-17a-hydroxypregnane-3,20-dione; 4-chloro-11a-valeryloxy a hydroxypregnane-3,20-dione; 4 chloro-l1a-hexanoyloxy-17a-hydroxypregnane-3,ZO-dione; 4-chloro 11a heptanoyloxy- 17a-hydroxypregnane-3,20-dione; 4-chloro-1la-octanoyloxy-17a-hydroxypregnane-3,20-dione; and the like.

The 4 chloro-11a-acyloxy-17a-hydroxypregnane-3,20- diones may be converted to cortisone acetate by brominating at the 21-position using bromine in acetic acid to produce the 21-bromo-4-chloro 11cc acyloxy-l7ot-hydroxypregnane-3,20-diones, dehydrohalogenating with pyridine to remove hydrogen chloride and obtain 21-b1'0I110-11ocacyloxy-17ot-hydroxy-4-pregnene-3,20-diones, hydrolyzing the 21-bromine and the lla-acyloxy group to produce 1la,17a,21-trihydroxy-4-pregnene 3,20 dione using sodium hydroxide in aqueous alcohol, acetylating the 21- hydroxyl group with one equivalent of acetic anhydride in pyridine to produce 2l-acetoxy-11a,17a-dihydroxy-4- pregnene-3,20-dione, and mildly oxidizing the Ila-hydroxy group with chromic acid in acetic acid to produce an eleVen-keto group.

Example l2.4-chl0r0-21-bromo-11 a,17ot-dihydrxypregnane-3,20-di0ne Following the method of Example 6, 21-bromo- 311,11a,17a-tIihYdIOXYPIEgHEIII-Z0-0116 (Preparation 19) gives 4 chloro-21-bromo 11,17a dihydroxypregnane- 3,20-dione in excellent yield. In the same manner 4- chloro-21-bromo-11a,17a-dihydroxypregnane 3,20-dione is obtained from 21-bromo-3;8,11u,17a-trihydroxypregnan--one (Preparation 21).

Mild oxidation of the llwhydroxy group of 4-chloro- 21-bromo-11ot,17a-dihydroxypregnane 3,20 dione gives 4-chloro 21 bromo-17u-hydroxypregnane-3,11,20-trione which can be converted to cortisone acetate as shown in Example 6.

Example 13.4-chl0r0-21-br0m0-1 7a-hydroxypregnane-3,11 ,ZO-trione According to the procedure of Example 9, 21-bromo- ,11B,17u-trihydroxypregnan 20 one (Preparation 20) is converted to 4-ch1oro-21-bromo-17a-hydroxypregnane- 3,11,20trione in essentially a quantitative yield; melting point 168 to 174 degrees centigrade.

In the same manner 21-bromo-3B,115,17a-trihydroxypregnan-ZO -one (Preparation 22) yields 4-ch1oro-21- bromo-17a-hydroxypregnane-3,11,20-trione identical with the product of Example 6, and which may be converted to cortisone acetate as shown in Example 6.

Example 14.4-chl0r0-21-br0m0-1 1 u-acetoxy-I 7ahydr0xypregnwne-3,20-dione 21-bromo-11 x-acetoxy 30,17a dihydroxypregnan-ZO- one is treated with tertiary-butyl hypochlorite according to the method of Example 3 to obtain 4-chloro-21-bromo- 11a acetoxy-l7a-hydroxypregnane-3,20-dione. Use of the starting compound 21-bromo-11a-acetoxy-3fi,17a-dihydroxypregnan-ZO-one also gives 4-ch1oro-2 l-bromo- 11wacetoxy-l7a-hydroxypregnane 3,20 dione in high yield.

In the same manner other 4-chloro-21-bromo-11aacyloxy-l7a-hydroxypregnane 3,20 diones are prepared from the corresponding 21-bromo-11a-acyloxy-3u(or fi),- l7a-dihydroxypregnan 20 ones, including 4-chloro-21- bromo 11ot-formyloxy-l7oc-hydroxypregnane-3,20-dione; 4 chloro 21 bromo-11ot-propionoxy-l7a hydroxypregnane-3,20-dione; 4-chloro-21-bromo-1 1 a-butyryloxy-17ahydroxypregnane 3,20-dione; 4-chloro 21 bromo-11avalerlyoxy-17whydroxypregnane-3,20-dione; 4-chloro-21- bromo-1 la-hexanoyloxy 17oz hydroxypregnane-3,20-dione; 4-chloro-21-brorno-1 1ot-heptanoyloxy-17a-hydroxypregnane-3,20-dione; 4-chloro 21 bromo-1 la-octanoyloxy-17u-hydroxypregnane-3,20-dione; and the like.

4-chloro 21 bromo 11oz acyloxy-lh-hydroxypregnane-3,20-diones may be converted to cortisone acetate as shown in Example 11.

Example 15.4,21 -dichl0r0-1 I 11,] 7ot-dihydr0xypregnane-3,20-di0ne 21-ch1orao-3u,11a,17u-trihydroXypregnan-ZO-one (Preparation 25) is converted, according to the method of Ex- 1&3 ample 1, to 4,21-dichloro-11u,17ot-dihydroxypregnane- 3,20-dione, the weight of steroid product being about the same as the weight of starting steroid.

In the same manner other 4,21-dichloro-1l-oxygenated- 17ot-hydroxypregnane-3,20-diones are prepared from corresponding 21-chloro 11 oxygenated 3,17wdihydroxypregnan-ZO-ones, including 4,21-dichloro-1lot-formyloxy- 17a-hydroxypregnane-3,20-dione; 4,2 l -dichloro-1 lot-PIO- pionoxy-17a-hydroxypregnane-3,ZO-dione; 4,21-dichloro- 11a-butyryloxy-17ot-hydroxypregnane 3,20 dione; 4,21- dichlorodlot-valeryloxy 17a hydroxypregnane-3,20-dione; 4,21-dichloro-1lm-hexanoyloxy 171x hydroxypregnane-3,20-dione; 4,2l-dichloro 11a heptanoyloxy-17ahydroXypregnane-3,20--dione; 4,2l-dichloro-1lwoctanoyloxy-17a--hydroxypregnane-3,20-dione; and the like.

The 21-chloro derivative may be converted to cortisone acetate in the same manner as the 21-bromo derivatives of Example 12 through Example 14.

Example 16. 4chl0r0 2i acetoxy 11st,]7zx dillydroxypregnanc'3,20-di0ne Using the method of Example 1, 17ot-trihydroxypregnan-2Gone (Preparation 26) gives almost the theoretical weight of 4-chioro-21-acetoxy- 1lot,17a-dihydroxypregnane-3,ZO-dione. In the same manner 21-ZlC6t0Xy-3fi,l10;,17oc-t1lilYCll'0XY pregnan 20- one (Preparation 28) is converted to 4-chloro-2l-acetoxy- 1 1a,17ct-dihydroxypregnane-3,ZO-dione.

Other 4 chloro -21- acyloxy 1le,l70t clihydroxypregnane-3,20-diones are prepared from the appropriate 21-acyloxy 3u(or ,8), lloc,l7c trihydroxypregnan 20- ones in the same manner, including 4-chloro-21-formyloxy 1104,1711 dihydroxypregnane 3,20 dione; 4- chloro 21 propionoxy 1.1a,17a dihydroxypregnane- 3,20 dione; 4 chloro 21 butyryloxy lla,17a-dihydroxypregnane-3,20 dione; 4 chloro 21 valeryloxy- 1106,17OL dihydroxypregnane 3,20 dione; 4 chloro- 21 hexanoyloxy 110.,17a dihydroxypregnane 3,20- dione; 4 chloro 21 heptanoyloxy 11et,l70. dihydroxypregnane 3,20 dione; 4 chloro 21 octanoyloxy- 11a,17ot-dihydroxypregnane-3,20-dione; and the like.

4 chloro 2l acyloxy 1104,170; diihydroxypregnane- 3,20-diones are oxidized with chromic acid in acetic acid under mild conditions to obtain 4-chloro-2l-acyloxy-17uhydroxypregnane-3,11,20-triones which are convertible to cortisone acylates as shown in Example 3 for cortisone acetate preparation.

2i-acetoxy-3a,11a,

Example 17. 4 chloro 21 acetoxy 17cc hydroxypregnnne-3,11,20-lrione 21 acetoxy 3a,l1;3,17u trihydroxypregnan 20- one (Preparation 27) is treated with about 4.2 molar equivalents of tertiary-butyl hypochlorite according to the method of Example 9 to give nearly the theoretical quantity of 4-chloro-2 1 -acetoxy- 1 7u-hydroxyp regnane- 3,11,20-trione; melting point 233-237 degrees centigrade. The same product is obtained in the same manner -start ing with 21-acetoxy-35,11,6,17a-trihydroxypregnan-ZO- one.

In the same manner other 4-chloro-2l-acyloxy-llahydroxy-pregnane-3,11,20-trioncs are prepared from cor responding 21-acyloxy-3a(.or fi),1l/i,17ot trihydroxypregnan 20 ones, including 4 chloro 21 forrnyloxy- 17cc hydroxypregnane 3,11,20 triones; 4 chloro 21- propionoxy 17a hydroxypregnane 3,11,20 triones; 4 chloro 21 butyryloxy 17a hydroxypregnane- 3,11,20 triones; 4 chloro 2l valeryloxy 17cc hydroxypregnane 3,11,20 triones; 4 chloro 21 hexarioyloxy 17cc hydroxypregnane 3,11,20 triones; 4 chloro 21 heptanoyloxy 17cc hydroxypregnane- 3,11,20 triones; 4 chloro 2l octanoyloxy 17oz hydroxypregnane-3,11,20-triones; and the like.

4 chloro 21 acyloxy 1711 hydroxypregnane- 3,11,20-triones are convertible to cortisone :acylates as shown in Example 3 for cortisone acetate preparation.

Example 18. 4 chloro 1100,21 diacetoxy 1700- hydrxypregnane-3,ZO-diOne Treating 1100,21 -diacetoxy-3 00,1700-dihydroxypregnan- -one (Preparation with tertiary butyl hypochlorite according to the procedure of Example 1 gives high yields of 4 chloro 1100,21 diacetoxy 1700 hydroxypregnane-3,20-dione. In the same manner 1100,21-diacetoxy- 31?,1700-di11ydroxypregnan-20-one (Preparation 31) is converted to 4-chloro-1100,21-diacetoxy-1700-hydroxypregname-3,20-dione in comparable yield.

Other 4-chloro 1100,21 diacyloxy-17c0 hydroxypregnane-3,20- diones are prepared from 1l00,21-diacyloxy- 300(or ,8),1700-dihydroxypregnan-ZO-ones in the same manner, including 4-chloro-l100-acetoxy-21-formyloxy- 1700 hydroxypregnane 3,20 dione; 4 chloro 1100- acetoxy 21 propionoxy 1700 hydroxypregnane-3,20- dione; 4 chloro 1100 'acetoxy 21 butyryloxy 1700- hydroxypregnane 3,20 dione; 4 chloro 1100 acetoxy- 21 valeryloxy 1700 hydroxypregnane 3,20 dione; 4 chloro 1100 acetoxy 21 hexanoyloxy 1700 hydroxypregnane 3,20 dione; 4 chloro 1100 acetoxy- 21 heptanoyloxy 170. hydroxypregnane 3,20 dione; 4 chloro 1100 acetoxy 21 octanoyloxy 1700 hydroxypregnane 3,20 dione; 4 chloro 1100,21 diformyloxy 1700 hydroxypregnane 3,20 dione; 4- ch-loro 1100,21 dipropionoxy 1700 hydroxypregnane- 3,20 dione; 4 chloro 1100,21 dibutyryloxy 17cchydroxypregnane 3,20 dione; 4 chloro 1100,21 dihexanoyloxy 1700 hydroxypregnane 3,20 dione; 4- chloro 1100,21 dioctanoyloxy 1700 hydroxypregnane- 3,20 dione; 4 chloro 1100 propionoxy 21 acetoxy- 1700-hydroxypregnane-3,2O-dione; and the like.

Treatment of 4-chloro-1100,21-diacy1oxy-1700-hydroxypregnane-3,20-di-ones with semicarbazide hydrochloride followed by pyruvic acid gives l100,21-diacyloxy-1700- hydroxy-4-pregnene 3,20-diones. Saponification of these diacyloxypregnenes with sodium hydroxide in aqueous alcohol gives 1la,1700,2l-trihydroXy-4-pregnene-3,20-dione which may be converted to cortisone acetate as shown in Example 11.

Example 19.4-chloropregnane-3,20-di0ne One gram of 300-hydroxypregnan-20one dissolved in fifty milliliters of tertiary-butyl alcohol containing 1.5 milliliters of water and 0.4 milliliter of concentrated hydrochloric acid is admixed with 0.85 gram of tertiarybutyl hypochlorite, and the resulting mixture is allowed to stand at room temperature with occasional shaking. After about two hours the product begins to precipitate and is recovered by filtration; weight 0.4 gram; melting point 178-183 degrees Centigrade. An additional 0.5 gram of 4-chloropregnane-3,20-dione is recovered from the filtrate by evaporating the solution to dryness.

In the same manner as described in Example 1 through Example 19, other 3-hydroxysteroids are converted to 4-chloro-3-ketosteroids using tertiary-butyl, tertiary-amyl, or other organic hypochlorite such as, for example, propyl hypochlorite, hexyl hypochlorite, octyl hypochlorite, or the like. Steroids thus-produced, which may be dehydrohalogenated as shown in the above examples to give A -3-ketostreroids, include the following: coprostanol or epicoprostanol gives 4-chlorocoprostanone which on dehydrohalogenation gives the known A -cholestenone; 300(01' 8)'-hydroxy-21-acetoxypregnane-11,20-dione or 300(01' B),11/3-dihydroxy-2l-acetoxypregnan-ZO-one gives 4-chloro-21-acetoxypregnane-3,11,20-trione which on dehydrohalogenat-ion yields the known 21-acetoXy-4- pregnene 3,11,20 trione; 300(or 5) hydroxy 17-isoetiocholanic acid gives 4-chloro-3-keto-17-isoetiocholanic acid which on dehydrohalogenation yields the known 3- keto-17-iso-A -etiocholenic acid; 300(or 5) hydroxypregnane 11,20 dione gives 4 chloropregnane 3,11,20- trione which on dehydrohalogenation yields the known 4-pregnene-3,1 1,20-trione; 300(or ,8) ,1 1 fl-dihydroxypregnan-20-one also gives 4-chloropregnane-3,11,20-trione; and other like examples.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the scope of the appended claims.

We claim: 1. A compound of the formula ?Hz-R3 n wherein R1 is a member of the group consisting of 00-hydroxy and 00-lower-a1kanoyloxy; R2 is a member of the group consisting of hydrogen and 00-hydroxy; R3 is a member of the group consisting of hydrogen, chlorine, bromine, and lower-alkarroyloxy; and wherein only one of R2 and R3 can be hydrogen.

2. 4 chloro 1100,1700 dihydroxy 21 lower alkanoyloXypregnane-3,20-dione.

3. 4 chloro 21 bromo 1100 loweralkarroyloxy- 1700-hydroxypregnane-3,2O-dione.

4. 4 chloro 1100,21 di (lower-alkanoyloxy) 1700- hydroxypregnane-3,20-dione.

5. 4 ch'loro 1100,1700 dihydroxy 21 acetoxypregnane-3,20-dione.

- 6. 4 chloro 21 bromo 1100 acetoxy 1700 hydroxypregnane-3,20-dione.

7. 4 chloro 1100,21 diacetoxy 1700 hydroxypregnane-3,20-dione.

8. 4 chloro 1100,1700 dihydroxypregnane 3,20 dione.

9. 4 chloro 1100,1700 dihydroxy 21 bromopregnane-3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS 2,440,874 Reichstein May 4, 1948 

1. A COMPOUND OF THE FORMULA 